EP0690065B1 - Halogenated biphenyl-2,2'-diyl-bis-diphenylphosphines, their preparation and use - Google Patents

Description

The present invention relates to halogenated biphenyl-2,2'-diyl-bisdiphenylphosphines, their manufacture and their use. Mono- and diphosphines are of considerable importance as ligands in Transition metal-catalyzed organic reactions. In recent years are particularly interested in homochiral mono- and diphosphines Ligands in transition metal-catalyzed enantioselective reactions found, e.g. in rhodium (I) -, ruthenium (II) - and iridium (I) - catalyzed asymmetric hydrogenations of prochiral alkenes, ketones and imines, in Palladium-catalyzed nucleophilic allylic substitutions and Heck coupling reactions, in rhodium (I) catalyzed hydrosilylations, Hydroboration and hydroformylation of prochiral alkenes and Hydrosilylations of ketones and imines, as well as in rhodium (I) -catalyzed asymmetric isomerizations of allylamines to the corresponding ones Enamines.

It is striking that in the known applications both achiral Phosphines in transition metal catalyzed reactions, as well as in all of the above mentioned examples for the use of homochiral phosphines in the catalytic asymmetric synthesis (Zassinovich et al., S.Chem.Rev. 1992, 92, 1051-1069, or EP-A-398 132) and in tables of approx. 200 different homochiral phosphines, phosphinites and Amidophosphines tested in asymmetric synthesis, all phosphines used are electron rich. Have the phosphines mentioned the disadvantage that some reactions catalyzed with their help are poor and in particular with insufficient enantioselectivity.

Furthermore, EP 0 643 065 A1, which is a document in the sense of Article 54 (3) EPC, describes compounds that correspond to the compounds of the present Invention are similar.

Surprisingly, it has now been found that certain electron poor Systems such as halogenated biphenyl-2,2'-diyl-bis-diphenylphosphines in some Transition metal-catalyzed reactions the conventional electron-rich Mono- and diphosphines in terms of reaction yield, catalytic Activity or enantioselectivity are superior.

in der die Phenylringe des Biphenylmoleküls mit bis zu 6 zusätzlichen Fluor- und/oder Chloratomen substituiert sein können.The present invention accordingly relates to the compounds of the formula II

in which the phenyl rings of the biphenyl molecule can be substituted with up to 6 additional fluorine and / or chlorine atoms.

The compounds of the formula II in which the phenyl rings are substituted with up to four fluorine and / or chlorine atoms, in particular with up to two fluorine and / or chlorine atoms, are preferred. The compounds of formula II have a very special meaning.

The present invention relates to the compounds mentioned both in the racemic form and in the chiral form, which are to be exemplified by the following formulas, which show very particularly preferred compounds.

wobei X = F mit Cl₂Si(CH₃)H, NBu₃, in einem organischen Lösungsmittel, vorzugsweise Xylol unter Inertgas, vorzugsweise Stickstoff umgesetzt wird oder alternativ mit HSiCl₃ und NBu₃ in einem organischen Lösungsmittel, vorzugsweise Xylol, unter Rückfluß gekocht wird wobei die Verbindung der Formel II entsteht und wobei die Phenylringe des Biphenylmoleküls mit bis zu 6 zusätzlichen Fluor und/oder Chloratomen substituiert sein können.The present invention further provides the process for the preparation of the compounds of the formula II, which is characterized in that a compound of the formula 4

where X = F is reacted with Cl ₂ Si (CH ₃ ) H, NBu ₃ in an organic solvent, preferably xylene under an inert gas, preferably nitrogen, or alternatively with HSiCl ₃ and NBu ₃ in an organic solvent, preferably xylene, boiled under reflux is where the compound of formula II is formed and where the phenyl rings of the biphenyl molecule can be substituted with up to 6 additional fluorine and / or chlorine atoms.

in einem inerten Lösungsmittel, vorzugsweise DMF, unter Zusatz eines Übergangsmetalls, vorzugsweise Cu, erhitzt wird, wobei die Verbindung der Formel 3 in 4-, 5- und/oder 6-Stellung mit bis zu 3 Fluor- und/oder Chloratomen substituiert sein kann.The compounds of formula 4 appearing as an important intermediate in chiral and racemic form also belong to the subject of the present invention. The present invention furthermore relates to the process for the preparation of the compound of the formula 4, which is characterized in that a compound of the formula 3

is heated in an inert solvent, preferably DMF, with the addition of a transition metal, preferably Cu, it being possible for the compound of the formula 3 to be substituted in the 4-, 5- and / or 6-position by up to 3 fluorine and / or chlorine atoms ,

mit Lithiumdiisopropylamid in einem inerten Lösungsmittel, vorzugsweise in THF, und anschließend mit Jod umgesetzt wird, wobei die Verbindungen der Formeln 2 und 3 in 4-, 5- und/oder 6-Stellung mit bis zu 3 Fluor- und/oder Chloratomen substituiert sein können.The present invention furthermore relates to the process for the preparation of the compound of the formula 3, which is characterized in that a compound of the formula 2

with lithium diisopropylamide in an inert solvent, preferably in THF, and then reacted with iodine, the compounds of the formulas 2 and 3 being substituted in the 4-, 5- and / or 6-position with up to 3 fluorine and / or chlorine atoms can.

A process for the preparation of compounds according to the invention is shown schematically below, naming preferred parameters.

The above procedures relate to the racemic compounds. The individual chiral forms of the compounds mentioned can be obtained by conventional racemate separation processes. A preferred separation process is shown by the scheme below. The following explanation of features according to the invention is carried out using the numerical designation of the compounds from scheme 2.

The resolution of (R / S) -5 to (S) - (+) - 5 takes place with 75% of the theoretical yield and to (R) - (-) - 5 with 95% of the theoretical yield. The optical purity is determined without a doubt by Chiral phase HPLC analysis of the corresponding bis (phosphine oxides) (S) - (-) - 4 and (R) - (+) -. 4 The absolute configuration is by single crystal X-ray structure analysis secured by (S, S) - (-) - 10.

The subject of the present invention also includes the Rh (I) -, Ru (II) -, Pd (II) and Pd (0) complexes of the compounds of the formula II,

Their preparation by reacting the compounds of formula II with appropriate complexes of these metals with easily displaceable ligands also the subject of this invention.

Z, Z-1,5-cyclooctadiene (COD), norbornadiene (NBD) or acetylacetonate (Acac) are preferred as such easily displaceable ligands. The corresponding transition metal complexes are commercially available or can be easily prepared in a known manner. The examples in this application (see asymmetric hydrogenation and asymmetric hydroboration / oxidation) contain specific rules for this procedure.
The homochiral palladium dichloride complexes with compounds of the formula II can, as shown in Scheme 2, also be obtained from the diastereomeric palladium complexes of the formula 10 by HCl-induced cleavage of the N, N-dimethyl-alpha-phenylethylamine ligand.

In addition, an object of the present invention is the use of the compounds of the invention as catalysts. The invention Catalysts are particularly suitable for the catalysis of organic addition, Substitution, rearrangement and coupling reactions. The optically pure Diphosphines 5 and their palladium dichloride complexes 11 are thermal and chemically unusually stable. For example, solutions from homochiral 5 have not been thermally racemized so far. Even after that Heating a solution of (S) - (+) - 5 in tetralin under reflux for 2.5 hours (Bp 207 ° C) in an argon atmosphere, is the specific rotation unchanged and chiral phase HPLC analysis of the corresponding phosphine oxide 4 still gives 100% ee. The enantiomers of 11 (mp. 310-312 ° C) after stirring for 16 hours in a solution of excess Potassium cyanide in water / methanol / dichloromethane unchanged recovered. There is no cleavage to the free diphosphine and Kaliumtetracyanopalladat. The extremely high thermal configuration stability of the homochiral diphosphine 5 and the high thermal and chemical Stability of its transition metal complexes (such as 11) is essential Basis for unusually wide range of uses of the latter as Organic reaction catalysts. The unusually high resistance against thermal racemization guarantees the maintenance of the full optical Induction of appropriate catalysts even at high reaction temperatures. The high chemical resistance enables the use of the catalyst in principle in the presence of unusually aggressive reagents.

The advantages of the generally usable catalysts are explained below using specific, particularly preferred examples. The specific rotation of, for example, the optically pure diphosphine (S) - (+) - 5 (compound of formula II) varies dramatically in different solvents (Table 1). For example, the direction of optical rotation is reversed from + 114.9 ° to -73.9 ° when tetralin is substituted for the toluene solvent. The importance of this hitherto unknown phenomenon for the asymmetric catalysis caused by corresponding transition metal complexes has not yet been clarified. The fact mentioned allows the optical induction to be influenced strongly and specifically by solvent variation and to produce the reaction product with the same catalyst in both absolute configurations, depending on which solvent is used. Specific rotation [a] _D ²⁵ of (S) - (+) - 5, measured in different solvents. [α] _D ²⁵ , (S) - (+) - 5 c solvent +153.3 1:02 THF +145.3 00:47 dioxane +123.7 1:03 dichloromethane +114.9 0.99 toluene +95.5 0.73 mesitylene +46.7 1:04 chloroform +21.4 0.64 o-xylene -73.9 00:46 tetralin

The rhodium (I) complex of (R) - (-) - 5 has high catalytic activity and enantioselectivity, for example in the hydroboration of prochiral olefins. The hydroboration of p-methoxystyrene 12 with 2 equiv. Catecholborane in THF at 0 ° C in the presence of 2 mol% of an in situ catalyst made from (1,5-cyclooctadiene) (2,4-pentanedionato) rhodium (I) and (R) - (-) - 5 is within 1.5 hours quantitative. Oxidation with excess hydrogen peroxide at 25 ° C gives 78% of the Markownikov product 1- (4-methoxyphenyl) ethanol 13 [77.8% ee of the (R) configuration] and 22% of the anti-Markownikov product 4-methoxyphenethyl alcohol 14 (Scheme 3). The presence of the rhodium (I) complex of the electron-deficient, homochiral diphosphine 5 thus drastically lowers the activation energy of the hydroboration, reverses the anti-Markovnikov selectivity of the hydroboration to a Markovnikov selectivity and delivers the product alcohol even in the case of the technically easily realizable one Reaction temperature of 0 ° C in a much higher optical purity than electron-rich diphosphines at -70 to -20 ° C. At 0-25 ° C, electron-rich diphosphines no longer provide significant induction.

The rhodium (I) complex of (R) - (-) - 5 catalyzes hydrogen additions C = C - double bonds at high hydrogen pressure. 2-Benzylidosuccinic acid-4 [(4-BOC-amino) -1-piperidide] 37 is at 25 ° C under 1 bar of hydrogen in the presence of 1 mol% of the in situ catalyst Di-µ-chloro-bis (cycloocta-1c, 5c-diene) rhodium (I) and (R) - (-) - 5 not hydrogenated. On in situ Rh (I) complex of the homochiral diphosphine (R) - (-) 5 causes at high Hydrogen pressure asymmetric hydrogenation (see the examples).

The palladium complexes of (R / S) -5 with palladium chloride or palladium acetate give better yields than corresponding palladium complexes electron-rich mono- or diphosphines in aryl-aryl couplings of Arylboronic acid esters with aryl halides in aqueous / organic Two-phase mixture (Suzuki coupling). They also make better ones Yields of Heck-type aryl vinyl couplings. The Palladium catalysts (S, S) - (-) - 10, (S, R) - (+) - 10, (S) - (-) - 11 and (R) - (+) - 11 result in superior chemical and optical yields in asymmetric allylic substitutions, Heck couplings and ring closure reactions.

Examples

Reagents, devices and general methods: acetone (99.5%, Riedel-de Haën), 1,2-bis (diphenylphosphine) ethane (99%, Aldrich), 1-bromo-3-fluorobenzene (> 99%, Aldrich) , n-butyllithium (15% solution in hexanes, 1.6 N, Chemetall Gesellschaft), (-) - (2R, 3R) -2,3-O, O'-dibenzoyltartaric acid and its (+) - (2S, 3S) enantiomer (> 99%, Fluka), catecholborane (1.0 N solution in THF, Aldrich), (1,5-cyclooctadiene) (2,4-pentadionate) rhodium (I) (99%, Aldrich) , Di-µ-chloro-bis [(cycloocta-lc, 5c-diene) rhodium (I)], (S) - (+) - di-µchloro-bis {2- [1- (dimethylamino) ethyl ] phenyl-C, N} dipalladium (9) (98%, Aldrich), dichloromethane (99.8%, Riedel-de Haen), dichloromethylsilane Cl ₂ Si (CH ₃ ) H (97%, Janssen), diethyl ether (> 99%, Hoechst), hydrogen peroxide (35% aqueous solution, Riedel-de Haën), iodine (99.8%, Riedel-de Haën), mesitylene (99%, Fluka), methanol (99.5%, 0.2 % H ₂ O, Riedel-de Haën), potassium hexafluorophosphate (> 98%, Fluka), tetralin (99%, Aldrich), toluene (> 99%, <0.03% H ₂ O, Aldrich), tri-n- butylamine (98%, Merck-Sch uchardt), trichlorosilane (99%, Aldrich), o-xylene (99.5%, Riedel-de Haën) were used as purchased.

Chlorodiphenylphosphine ClPPh ₂ (technical, 95%, Aldrich) (boiling point 98-100 ° C / 0.2 Torr) and p-methoxystyrene (97%, Aldrich) (boiling point 41-42 ° C / 0.5 Torr) became immediate Distilled under vacuum before use. Diisopropylamine (99%, Aldrich) and diisopropyl ether (> 99%, Hoechst) were distilled from calcium hydride in an argon atmosphere immediately before use (Karl Fischer titration gave <0.01% H ₂ O in iPr ₂ O and ≤ 0.05% H ₂ O in iPr ₂ NH). N, N-Dimethylformamide (DMF) was left in a sealed flask over activated 4A molecular sieves for several days and then distilled under vacuum. Tetrahydrofuran (THF) was passed through ICN aluminum oxide B (activity 1.1 g / 3 ml THF) for drying immediately before use (Karl Fischer titration gave <0.01% H ₂ O).

Copper powder (99.8%, Riedel-de Haën) was activated using the following procedure:
260 g of copper powder was placed in a solution of 52 g of iodine in 2.6 l of acetone and the mixture was stirred for 10 minutes. The copper was filtered through a Buchner funnel and stirred for 10 minutes in a solution of 650 ml of concentrated hydrochloric acid in 650 ml of acetone. The copper powder was filtered, washed with 3 × 200 ml acetone and dried under vacuum in a desiccator.

All reactions were carried out in a dry glass apparatus in one Argon atmosphere driven.

The melting points (mp) were measured using a Buchi capillary melting point device (according to Dr. Tottoli) and are not corrected. HPLC: Kontron 420 pump with Kontron 425 gradient generator, Kontron 360 autosampler (20 µl injection loop), Kontron 432 HPLC UV detector and Kontron 450-MT2 data processing system or alternatively Spectra Physics SP 4200 pump / 8750 Organizer (10µl injection loop) with SP 8700 solvent dosing system, Spectra 100 UV-Vis detector and SP 4100 computing Integrator. TLC: precoated with silica gel 60 F-254 (E. Merck) 5 × 10 cm glass plates; Representation of stains with universal Camag UV lamp (254 nm). Ultrasonic cleaning bath: Elma Transsonic TS540.

¹ H-NMR (internal standard TMS): Varian Gemini 200 (200 MHz), Bruker AM 400 (400 MHz) and Bruker ARX 500 (500 MHz). ¹³ C-NMR (internal standard TMS): Bruker AM 270 (67.93 MHz) and Bruker ARX 500 (125.77 MHz). ¹⁹ F-NMR (internal standard fluorotrichloromethane): Bruker AC 100 (94.2 MHz), Varian Gemini 200 (188.14 MHz), Bruker AM 400 (376.50 MHz) and Bruker ARX 500 (470.59 MHz). ³¹ P-NMR (external standard 80 aqueous phosphoric acid): Bruker AM 270 (109.35 MHz), Bruker AM 360 (145.79 MHz) and Bruker ARX 500 (202.46 MHz). The specified δ and J values for all compounds except (R / S) -4, (S) - (-) - 4 and (R) - (+) - 4 correspond to the usual first-order analysis of the spectra. All NMR spectra of (R / S) -4, (S) - (-) - 4 and (R) - (+) - 4 were obtained using decoupling methods and the ¹ H- ¹³ C NMR correlation (hsqc ) fully analyzed. IR: Perkin Elmer 683 spectrometer. MS: a) "Fast atom bombardment" positive ionization (+ FAB): VG ZAB SEQ; NBA denotes p-nitrobenzyl alcohol. b) "dissociation chemical ionization" (DCI): Kratos MS 80. c) "positive electrospray ionization" (+ ESI): VG BIO-Q; Acetonitrile / water (1: 1) + 0.5% formic acid. Optical rotation was determined on a Perkin-Elmer 241 polarimeter using a 10 cm long micro cuvette.

The X-ray structures were determined on the basis of single crystals sealed in Lindemann glass capillaries, using a computer-controlled four-circle diffractometer (R3m / V, Siemens). 25 reflections with > 4 ° (for 4 and S, S-10) or > 8 ° (for 7 ) were used to determine the cell dimensions. The phase problem was solved with the direct method, minimization of Σw (Fo ² -Fc ² ) ² , weighting scheme w according to the counting statistics.

(3-fluorophenyl) diphenylphosphine oxide (2)

A solution of 1-bromo-3-fluorobenzene (1) (298.7 g, 1.7 mol) in diisopropyl ether (4.0 l) was added to a 1.6 at -78 ° C within 30 min using a flexible needle N solution of n-butyllithium in hexanes (1060 ml, 1.7 mol) was added. The yellow suspension was stirred for a further hour at -78 ° C. Chlorodiphenylphosphine (394 g, 1.78 mol) was added dropwise over 20 minutes at -78 ° C to -60 ° C. The yellow solution was allowed to warm to 0 ° C over 2 hours, gradually becoming a white suspension. A saturated aqueous ammonium chloride solution (1.0 L) was added dropwise. The organic layer was separated, washed with brine (2 x 700 ml), dried with MgSO ₄ and then filtered. The solvent was evaporated in vacuo and the oily residue was dried under high vacuum until crystallization started and gave a pale yellow semi-solid (479 g, 1.71 mol, 100% yield). This crude product was oxidized to phosphine oxide without purification. An analytical sample was obtained by washing the crude product with methanol to give colorless crystals of (3-fluorophenyl) diphenylphosphine, mp 59-61 ° C, R _f 0.26 (cyclohexane) [R _f of 1: 0.73], ¹ H NMR (200 MHz, CDCl ₃ ): δ 6.84-7.17 (m, 3H), 7.20-7.60 (m, 11H); MS (DCI, CH ₃ OH): m / e (rel. Int.) 281 (M + H, 100), 280 (M, 83), 203 (MC ₆ H ₅ , 24); IR (KBr): 3070, 1602, 1580, 1475, 1437, 1415, 1216, 876, 791, 742, 694, 685 cm ^-1 .

In a suspension of the phosphine (476.5 g, 1.7 mol) in methanol (2.1 l) 35% aqueous hydrogen peroxide (183 ml, 2.1 mol) was added dropwise at <40 ° C. After stirring the clear yellow solution obtained for 10 min at 20 ° C., the TLC showed a quantitative reaction (ethyl acetate / isopropanol 20: 1; R _f 2: 0.44; phosphine: 0.75). A saturated aqueous solution of sodium sulfite (640 ml) and iN hydrochloric acid (300 ml) was added and the mixture was stirred until an iodine starch paper test indicated complete reduction of the excess hydrogen peroxide. Methanol was evaporated in vacuo and dichloromethane (4.0 L) was added with stirring. The organic layer was separated, washed with 2 × 1 l of saturated sodium bicarbonate solution and with 2 × 1 l of water. The organic phase was dried (MgSO ₄ ) and the solvent was evaporated in vacuo to leave a white powder (475 g). It was triturated with diisopropyl ether (900 ml) in an ultrasonic cleaning bath, filtered and washed again with diisopropyl ether (300 ml) and dried under vacuum: 441 g (1.49 mol, 88% yield based on 1 ), mp. 143-145 ° C. HPLC [250 × 4.6 mm Lichrosorb RP 18 7 μm, 1 ml / min (630 ml CH ₃ CN + 370 ml H ₂ O + 0.1% NH ₄ OAc), det .: 254 nm, t _ret 8 , 50 min] gave a purity of 98.1%. ¹ H NMR (200 MHz, CDCl ₃ ):  7.18 - 7.80 (m); MS (DCI, CH ₃ OH): m / e (rel.Int. 297 (M + H, 100) 296 (M, 11), 295 (MH, 13); IR (KBr): 3055, 1583, 1440, 1228, 1188, 1122, 1110, 725, 708, 700, 690, 542, 511 cm ^-1 .

(3-fluoro-2-iodophenyl) diphenylphosphine oxide (3)

Note: It is essential to use carefully dried glassware, THF and diisopropylamine at this step and to avoid excess iodine. Even the presence of the 0.2% H ₂ O contained in commercially available diisopropylamine affected the results (10-15% 2 and diiodide 6 were not converted in each case).

A solution of diisopropylamine (176 ml, 1.24 mol) in THF (1.0 l) was added with a 1.6 N solution of n-butyllithium in hexanes (769 ml, 1.23 mol) at -70 ° C. The solution was allowed to warm to -20 ° C and then cooled again to -70 ° C. This clear yellow LDA solution was converted into a cold (-78 ° C) suspension of 2 (296.3 g, 1.0 mol) in THF (2.0 1 ) entered. The mixture was stirred at -78 ° C for 15 min to give an orange-red suspension. A solution of iodine (254 g, 1.0 mole) in THF (1.0 L) was added dropwise at ≤ -70 ° C in 30 min, resulting in a yellow-orange thick suspension. It was allowed to warm to 0 ° C over 1.5 hours. A solution of sodium thiosulfate (74 g) in water (600 ml) was added, followed by the addition of brine (1.2 l). The organic phase was separated and washed with 3 × 1.2 l brine. It was dried (MgSO ₄ ) and the solvent was evaporated in vacuo. The residue was triturated with diisopropyl ether (1.0 l) in an ultrasonic cleaning bath (≈ 1 min). The solid was filtered and dried under vacuum to give a colorless powder (358g, 848 mmol, 85% yield), mp 155-157 ° C. HPLC [250 × 4.6 mm Lichrosorb RP18 7 μm, 1.5 ml / min (630 ml CH ₃ CN + 370 ml H ₂ O + 0.1% NH ₄ OAc), det .: 220 nm] gave 0.6 % 2 (t _ret 4.41 min), 97.8% 3 (t _ret 4.71 min), 1.6% 6 (t _ret 7.47 min). ¹ H-NMR (200 MHz, CDCl ₃ ): δ 6.97 (ddd, ³ J _{H, P} = 13 Hz, ³ J _{H, H} = 7 Hz, ⁴ J _{H, H} = 1 Hz, 1 H), 7.15 - 7.38 (m, 2H), 7.40 - 7.80 (m, 10H); ¹⁹ F { ¹ H} -NMR (94.2 MHz, CDCl ₃ ): δ -87.3 (d, ⁴ J _{F, P} = 6.8 Hz); ¹⁹ F-NMR (94.2 MHz, CDCl ₃ ): δ -87.3 (td, ⁴ J _{F, P} ≈ ³ J _{F, H} ≈7.0 Hz, ⁴ J _{F, H} = 5.2 Hz) ; MS (DCI): m / e (rel. Int.) 423 (M + H, 100); IR (KBr): 2920 (w), 1437, 1400, 1244, 1182, 1117, 791, 718, 697, 542, 520 cm ^-1 .

The characteristic spectral signals were observed for the products of test reactions containing [up to 15% diiodide 6 [due to traces of water in the reagents and an excess of iodine (1.13 equiv.)]: 1H-NMR (200 MHz , CDCl ₃ ): δ 6.68 (dd, ³ J _{H, P} = 12.5 Hz, ³ J _{H, H} = 9 Hz); ¹⁹ F { ¹ H} -NMR (94.2 MHz, CDCl ₃ ): δ -65.8 (d, ⁴ J _{F, P} = 5.9 Hz); ¹⁹ F NMR (94.2 MHz, CDCl ₃ ): δ -65.8 (≈t, ⁴ J _{F, P} = 5.9 Hz, ⁴ J _{F, H} = 5.7 Hz); MS (+ ESI): m / e 549 (M + H).

(RS) - (6,6'-difluoro-biphenyl-2,2'-diyl) bis (diphenylphosphine) ((R / S) -4)

A mixture of 3 (350 g, 829 mmol), activated copper powder (163 g, 2.56 mol, see reagents and devices) and DMF (1.7 1) became 1.5 at 140 ° C. (oil bath temperature) stirred for h. The mixture was cooled to ambient temperature and the solvent was evaporated to dryness in vacuo at 70 ° C. The residue was extracted by repeated stirring with hot dichloromethane (4 × 2 l). The filtered extracts were pooled and evaporated to dryness, and the residue was dried under high vacuum to give a solid (223 g, yield 91%) which, after HPLC [conditions as described for 3], from 92% 4 (t _ret 7.25 min) and 8% 2 (<0.1% 3 ). Ultrasound treatment in dichloromethane (1.3 l) for 1 min gave a colorless solid (173 g, yield 71%), mp. 280-282 ° C.,> 99.5% 4 . An analytical sample was obtained by recrystallization by refluxing dichloromethane / ethyl acetate (3: 1) to obtain crystals, mp 283-284 ° C. NMR spectra were identical to those of the optically pure compounds (S) - (-) - 4 and (R) - (+) - 4 (see below). MS (+ FAB, MeOH / NBA): m / e (rel.Int.): 591 (M + H, 100) 513 (M-Ph, 7), 389 (M-Ph ₂ PO, 17), 201 ( Ph ₂ PO, 27); IR (KBr): 3058 (w), 1436, 1422, 1240, 1206, 1192, 1117, 742, 695, 566, 532 cm ^-1 .

Crystals suitable for X-ray analysis were obtained by recrystallization from boiling toluene. Crystal of 0.31 x 0.18 x 0.17 mm ³ ; Cell dimensions: a = 26.570 (4), b = 12.840 (4), c = 20.296 (3) Å, β = 120.04 (1) °; C2 / c, Z = 8, D _x = 1.309 Mg / m ³ ; λ (Mo K _α ) = 0.7107 Å,  _max = 25.06 °, 5107 individual reflections, 3117 with (Fo)>4σ; 379 parameters, wR2 = 0.154 (all reflections), R1 = 0.046 (3117 reflections), S = 0.92, maximum and minimum in the differential Fourier synthesis: 0.46, -0.39 e / Å ³ .

(RS) - (6,6'-Difluoro-5-iodo-biphenyl-2,2'-diyl) bis (diphenylphosphine) (7)

The reaction of monoiodide 3 containing 14% diiodide 6 under the same Ullmann coupling conditions resulted in a product consisting of 89% 4 , 10% 7 and 1% of an unidentified component. 31.5 g of this mixture were chromatographed over 3 kg of RP18 silica gel (eluent methanol / water 1: 1) and, after recrystallization from hot dichloromethane / ethyl acetate (3: 1), gave 2.7 g of 7, colorless needles, mp. 272-274 ° C, HPLC (conditions as described for 3, _ret 11.69 min):> 99%. ¹ H-NMR (500 MHz, CDCl ₃ ): δ 6.78 (dd, ³³ J _{H, P} = 13.0 Hz, ³ J _{H, H} = 8.4 Hz, 1H), 7.06 (ddd, ³ J _{H, P} = 13.0 Hz, ³ J _{H, H} = 8.0 Hz, ⁴ J _{H, H} = 1.2 Hz, 1H), 7.12 (br t, ³ J _{H, F} ≈ ³ J _{H, H} ≈8.5 Hz, 1H), 7.30-7.36 (m, 5H), 7.40-7.48 (m, 6H), 7.50-7.56 (m, 2H) ), 7.58-7.68 (m, 8H), 7.70 (ddd, 1H); ¹⁹ F { ¹ H} -NMR (94.2 MHz, CDCl ₃ ): δ -89.6 (dt, ⁴ J _{F, P} = 6.3 Hz, ⁵ J _{F, P} = 0.9 Hz, ⁵ J _{F, F} = 0.9 Hz), -110.3 (dt, ⁴ J _{F, P} = 6.9 Hz, ⁵ J _{F, P} = 0.8 Hz, ⁵ J _{F, F} = 0.9 Hz) ; ¹⁹ F NMR (94.2 MHz, CDCl ₃ ): δ -89.6 (br t, ⁴ J _{F, P} = ⁴ J _{F, H} = 6.3 Hz), -110.3 (br qua, ⁴ J _{F, P} ≈ ³ J _{F, H} ≈ ⁴ J _{F, H} ≈7.0 Hz); ³¹ P { ¹ H} -NMR (109.35 MHz, CDCl ₃ ): δ +28.47 (d, ⁴ J _{P, F} = 6.3 Hz), +28.58 (d, ⁴ J _{P, F} = 6.9 Hz); MS (DCI, MeOH): m / e (rel. Int.) 717 (M + H, 85), 515 (M-Ph ₂ PO); IR (KBr): 3057 (w), 1438, 1393, 1203, 1118, 705, 695, 533 cm ^-1 . A baseline separation of the enantiomers of 7 [t _ret 20.34 (+) - isomer and 22.14 min (-) - isomer] was carried out on a 250 × 4.6 mm column of DNBPG Bakerbond with the eluent n-heptane / ethanol 15 : 1 received.

Crystals suitable for X-ray analysis were obtained by recrystallization from boiling dichloromethane. Crystal 0.45 x 0.45 = 0.3 mm ³ ; Cell dimensions: a = 10.462 (1), b = 14.579 (1), c = 20.467 (2) Å; P2 ₁ 2 ₁ 2 ₁ , Z = 4, D _x = 1.524 Mg / m ³ ; λ (MoK _α ) = 0.7107 Å,  _max = 28.06 °, 7569 individual reflections, 7063 with (Fo)>4σ; 488 parameters, wR2 = 0.065 (all reflections), R1 = 0.023 (7063 reflections), S = 0.67, maximum and minimum in the differential Fourier synthesis: 0.53, -0.26 e / Å ³ .

Attempt to resolve (R, S) -4 with (-) - (2R, 3R) -2,3-O, O'-dibenzoyltartarsäure

a) The solution of (2R, 3R) - (-) - di-O-benzoyltartaric acid (951 mg, 2.53 mmol) in ethyl acetate (6 ml) was added to the solution of (R / S) -4 (815 mg, 1.38 mmol) in boiling dichloromethane (15 ml) added. The solution was refluxed for 3 hours. No precipitate was formed. The solution was left at 20 ° C overnight. No precipitate was formed.

b) (2S, 3S) - (+) - Di-O-benzoyltartaric acid monohydrate (1.70 g, 4.50 mmol) and (R / S) -4 (2.00 g, 3.35 mmol) were in dichloromethane (30 ml) dissolved. n-Heptane (13 ml) was added dropwise with stirring. The cloudy mixture was left to stand for 30 minutes and two layers formed. The layers were separated and both were washed independently with 2N sodium hydroxide (2 x 15 ml) and with water (2 x 15 ml). The organic solutions were dried (MgSO ₄ ) and the solvents were evaporated under vacuum. Upper layer: colorless solid (0.98 g), (R / S) -4 (<1% ee) according to the optical rotation (365 nm, c = 0.56, CH ₃ OH) and HPLC of the chiral phase. Lower layer: colorless solid (0.75 g), (R / S) -4 (<1% ee) according to the optical rotation and HPLC of the chiral phase.

(RS) (6,6-difluoro-biphenyl-2,2'-diyl) bis (diphenylphosphine) ((R / S) -5)

a) By reduction of (RS) -4 with trichlorosilane: A suspension of (R / S) -4 (64.3 g, 109 mmol) in deoxygenated xylene (900 ml) was used to convert tri-n-butylamine (150 ml, 638 mmol) and trichlorosilane (43 ml, 426 mmol) added. The suspension was heated to reflux (138 ° C) and gave a clear solution. It was kept at gentle reflux for 18 hours. After a reaction time of 9 h, additional tri-n-butylamine (150 ml, 638 mmol) and trichlorosilane (10 ml, 99 mmol) were added. TLC (EtOAc / MeOH 19: 1) showed quantitative conversion of 4 (Rf 0.30) to 5 (Rf 0.86) and a small amount of monoxide (R _f 0.77). The reaction mixture was cooled to 0 ° C. Deoxygenated 30% aqueous sodium hydroxide solution (400 ml) and dichloromethane (500 ml) were added and the mixture was stirred at 60 ° C until the organic and aqueous layers became clear (30 min). The aqueous layer was removed via a cannula and the organic layer was washed with deoxygenated 30% aqueous sodium hydroxide solution (400 ml), water (3 x 400 ml) and brine (400 ml), dried (MgSO ₄ ), filtered and evaporated under vacuum. The residue was dried in a high vacuum, then dissolved in dichloromethane (1.1 l) and then cyclohexane (1.1 l) was added. The solution was filtered through a layer (30 cm high) of silica gel (35-70 µm, 850 g) and the layer was washed with dichloromethane / cyclohexane (1: 1, 3.0 l). The filtrates were evaporated under vacuum, and a colorless solid (48.0 g, 86.0 mmol, yield 79%), mp. 215-217 ° C., the HPLC (250 × 4.6 mm Nucleosil 120 C8 7 μm) , 1 ml / min 85% acetonitrile / 15% water, det. 254 nm, injection of 10 µl of a solution of 1.0 mg 5 and 5 ml CH3CN with ultrasound treatment, _ret 14.50 min) gave a purity of> 99 %. An analytical sample was obtained by recrystallization from boiling toluene / ethanol (4: 5): mp 222-223 ° C; ¹ H NMR (200 MHz, CDCl ₃ ) δ 6.83-6.98 (m, 4H), 7.10-7.40 (m, 22H); ¹⁹ F NMR (188.14 MHz, CDCl ₃ ): δ -112.6 (m); ³¹ P { ¹ H} -NMR (109.35 MHz, CDCl ₃ ): δ -12.70 (t, ⁴ J _{P, F} ≈ ⁵ J _{P, F} ≈9.3 Hz); MS (DCI, CHCl ₃ ) m / e (rel. Int.) 559 (M + H, 53), 373 (M-PPh ₂ , 100); IR (KBr): 3035 (w), 1562, 1446, 1432, 1417, 1234, 790, 742, 693 cm ^-1 .

b) By reduction of (R, S) -4 with dichloromethylsilane: In a cylindrical glass insert for a steel autoclave, (R / S) -4 (13.47 g, 22.8 mmol) in o-xylene (150 ml ) suspended. Argon was bubbled through the suspension for 10 minutes. Dichloromethylsilane (11.9 ml, 13.1 g, 114 mmol) was added, followed by tri-n-butylamine (28.4 ml, 22.2 g, 121 mmol). The argon-filled glass insert was placed in the autoclave. Nitrogen (5 bar) was injected, then the pressure was reduced very slowly. Nitrogen (100 bar) was injected and the autoclave was heated to an internal temperature of 150 ° C. for 86 h. The autoclave was allowed to cool to ambient temperature. The nitrogen pressure was then released and the glass insert removed. TLC of an aliquot of the dark brown reaction mixture, diluted with dichloromethane, indicated the clean formation of 5 , with the residues of 4 and monoxide moving close to the detection limit. All volatile components were evaporated (bath 60 ° C / <20 mbar). Methanol (100 ml) was added to the dark brown residue and the suspension was treated in an ultrasonic cleaning bath for 5 min. The solid was filtered, washed with methanol (20 ml) and dried under vacuum to give an off-white product (12.8 g, yield 100.5%), mp 213-220 ° C. Isopropanol (30 ml) was added and the suspension was sonicated for 1 min. The solid was filtered and dried under vacuum: colorless powder (11.7 g, 21.0 mmol, yield 92%), mp. 221-223 ° C; Spectra identical to those described under a) .

c) By reduction of (R / S) -7 with dichloromethylsilane: The reaction of (R / S) -7 (1.14 g, 1.60 mmol), dichloromethylsilane (918 mg, 7.98 mmol) and tri- n-Butylamine (1.55 g, 8.46 mmol) in o-xylene (15 ml) under the same conditions as described under b ) gave the crude product (908 mg, yield 102) after the same treatment and ultrasound irradiation in methanol (10 ml) %) as an off-white solid, mp. 213-219 ° C. Ultrasound radiation in isopropanol (2 ml) gave a colorless powder (808 mg, 1.45 mmol, yield 91%), mp 221-223 ° C; Spectra identical to those described under a ).

Resolution of (R / S) -5 via palladium complexes 10 {(S) -2- [1- (dimethylamino) ethyl] phenyl-C, N} [(S) - (6,6'-difluoro-biphenyl-2,2'-diyl) bis (diphenylphosphine)] palladium (II ) hexafluorophosphate (S, S) - (-) - 10

A suspension of (R / S) -5 (4.36 g, 7.38 mmol) and (S) - (+) - di-µ-chlorobis {2- [1- (dimethylamino) ethyl] phenyl-C, N} dipalladium (9) (2.19 g, 3.69 mmol) in deoxygenated methanol (430 ml) was stirred at 25 ° C for 2 h until an almost clear, pale yellow solution resulted. A very small amount of undissolved matter was removed by filtration. A solution of potassium hexafluorophosphate (680 mg, 3.69 mmol) in deoxygenated water (430 ml) was added dropwise. A pale yellow solid was precipitated and the suspension was stirred for 4 hours. The course of the reaction could be monitored by TLC (100% isopropanol; R _f (R / S) -5 : 0.72, (S, S) -10 : 0.57, (S, R) -10 : 0.37, 9: 0.00). The precipitates were collected by filtration, washed with 50% deoxygenated aqueous methanol solution (300 ml) and then with diethyl ether (150 ml). [While these washes were discarded, the original filtrate was kept for the isolation of (S, R) - (+) -10 (see next paragraph)]. The pale yellow solid was dried under vacuum to give the crude (S, S) -10 (3.33 g, 3.48 mmol, yield 94% of theoretical); M.p. 218-220 ° C (dec.); [α] _D 25 -198.6 (c 0.967, acetone). ¹ H NMR signals of its diastereomer (S, R) -10 could not be detected, but traces were observed by means of DC (diastereoselectivity> 98: 2). The crude complex was dissolved in deoxygenated acetone (40 ml) and diethyl ether (40 ml) was slowly added. The mixture was left in a sealed flask for 8 hours. The precipitate was collected by filtration and dried under vacuum: 2.83 g (2.95 mmol, yield 80% of the theoretical value) pale yellow solid, mp. 223-225 ° C (dec.), [Α] _D 25 -203 , 2 (c 0.98, acetone); ¹ H-NMR (200 MHz, acetone-d ₆ ) δ 1.36 (d, J = 6.5 Hz, 3H, NCHCH ₃ ), 1.68 (d, J = 2.5 Hz, 3H, NCH ₃ ), 2.68 (m, approx.t, J = 3.7 Hz, 3H, NCH ₃ ), 5.54 (qua, J = 6.5 Hz, 1H, NCHCH ₃ ), 6.32 (≈t, J = 7.0 Hz, 1H), 6.58 (≈qua d, J = 8.0 and 1.0 Hz, 1H), 6.68-6.86 (m, 4H), 7.06-8, 26 (m, 24H); ³¹ P { ¹ H} -NMR (145.79 MHz, acetone-d ₆ ) δ -143.7 (sept, ¹ J _{P, F} = 707 Hz, PF ₆ -), +11.5 (dd, ² J _{P, P} = 45 Hz, ⁴ J _{P, F} = 8 Hz), +35.3 (dd, ² J _{P, P} = 45 Hz, ⁴ J _{P, F} = 7 Hz); ¹⁹ F { ¹ H} -NMR (376.50 MHz, acetone-d ₆ , the left side of the PF ₆ doublet was set to -70 ppm in accordance with literature data for NaPF ₆ ) δ-70.9 (d, ¹ J _{F, P} = 707 Hz, 6F, PF ₆ -), -106.2 (ddd, ⁴ J _{F, P} = 7.3 Hz, ⁵ J _{F, F} = 5.9 Hz, ⁵ J _{F, P?} = 1.7 Hz), -106.4 (ddd, ⁴ J _{F, P} = 7.7 Hz, ⁵ J _{F, F} = 5.9 Hz, ⁵ J _{F, P?} = 1.7 Hz); MS (+ FAB, MeOH / NBA): m / e (rel. Int.) 817 (16), 816 (32), 815 (30), 814 (71), 813 (43), 812 (100), 811 (67), 810 (27), 809 (2), 808 (3) [the peaks m / e = 816, 814, 812, 811, 810, 808 correspond to the cation C ₄₆ H ₄₀ F ₂ NP ₂ Pd of the salt with the palladium isotopes (natural frequency) ¹¹⁰ Pd (43.2), ¹⁰⁸ Pd (97.7), ¹⁰⁶ Pd (100), ¹⁰⁵ Pd (81.3), ¹⁰⁴ Pd (40.1) and ¹⁰² Pd (3rd , 5)]; IR (KBr): 3060 (w), 1450, 1442, 1418, 841, 746, 697, 556, 502 cm ^-1 .

Crystal: 0.3 x 0.2 x 0.15 mm ³ ; Cell dimensions: a = 12.091 (1), b = 18.612 (4), c = 18.958 (2) Å; P2 ₁ 2 ₁ 2 ₁ , Z = 4, D _x = 1.391 Mg / m ³ ; λ (Mo K _α ) = 0.7107 Å,  _max = 25.0 °, 8124 individual reflections, 4722 with (Fo)>4σ; 533 parameters, wR2 = 0.076 (all reflections), R1 = 0.047 (4722 reflections), S = 0.83, maximum and minimum in the differential Fourier synthesis: 0.88, -0.61 e / Å ³ .

{(S) -2- [1- (dimethylamino) ethyl] phenyl-C, N} [(R) - (6,6'-difluoro-biphenyl-2,2'-diyl) bis (diphenylphosphine)] palladium (II )-chloride (S, R) - (+) - 10

The original filtrate from the preparation of (S, S) - (-) -10 (see above) was evaporated under vacuum to give a pale yellow solid (3.25 g, 3.83 mmol, yield 104% of theoretical); M.p. 162-165 ° C (dec); [α] _D 25 + 184.3 (c 1.02, methanol). ¹ H NMR signals of its diastereomer (S, S) -10 could not be detected, and no traces were observed with the DC (diastereoselectivity >> 99: 1). The crude complex was dissolved in deoxygenated methanol (40 ml) and refluxed for 2 minutes. Deoxygenated water (150 ml) was added and the mixture was left in the sealed flask for 8 hours. The precipitate was collected by filtration, washed with deoxygenated methanol / water (1: 8, 15 ml), water (30 ml) and dried under vacuum: pale yellow crystals (3.00 g, 3.54 mmol, 96% yield) mp 164-166 ° C (dec.), [Α] _D ²⁵ +208.0 (c 1.01, methanol); ¹ H-NMR (200 MHz, CD ₃ OD): δ 2.05 (d, J = 1.9 Hz, 3H, NCH ₃ ), 2.17 (m, approx. T, J ≈ 3.3 Hz, 3H, NCH ₃ ), 2.27 (d, J = 6.3 Hz, 3H, NCHCH ₃ ), 3.58 (qui, J = 6.3 Hz, 1H, NCHCH ₃ ), 6.26 (tdt, J = 7.5, 2.5 and 1.3 Hz, 1H), 6.44 (qua d, J = 7.5 and 0.8 Hz), 6.66-6.85 (m, 4H), 6.96-7.76 (m, 24H); ³¹ P { ¹ H} -NMR (145.79 MHz, CD ₃ OD) δ +10.72 (dd, ² J _{P, P} = 44 Hz, ⁴ J _{P, F} = 7.6 Hz), 33.21 (dd, ² J _{P, P} = 44 Hz, ⁴ J _{P, F} = 7.5 Hz); ¹⁹ F { ¹ H} -NMR (376.50 MHz, CD ₃ OD): δ -103.37 (qua, ⁴ J _{F, P} ≈ ⁵ J _{F, F} ≈6.8 Hz), -104.46 ( ≈ qua d, ⁴ J _{F, P} ≈ ⁵ J _{F, F} ≈6.8 Hz, ⁵ J _{F, P?} ≈2 Hz); MS (+ FAB, MeOH / NBA): identical to MS from (S, S) -10.

[(S) - (6,6'-difluoro-biphenyl-2,2'-diyl) bis (diphenylphosphine)] - dichloride palladium (II) (S) - (-) - 11

Deoxygenated 10 N hydrochloric acid (12 ml) was added to the refluxing solution of (S, S) - (-) -10 (1.12 g, 1.17 mmol) in deoxygenated acetone (20 ml). A yellow precipitate formed after a few minutes. The mixture was refluxed for 2 hours and then concentrated to 10 ml under vacuum. Deoxygenated water (100 ml) was added and nitrogen was bubbled through the suspension (25 ° C, 10 min). The solid was obtained by filtration and stirred with isopropanol / water (1: 1, 20 ml) for 5 minutes. The solid was filtered, washed with isopropanol / water (1: 1, 5 ml), dried under vacuum and gave bright yellow crystals (846 mg, 1.15 mmol, yield 98%), mp. 310-312 ° C (dec .), [α] _D 25 -311.9 (c 0.495, dichloromethane); the specific rotation was unchanged after the solution was left at ambient temperature for 8 days; ¹ H NMR (200 MHz, CDCl ₃ ): δ 6.66-6.86 (m, 4H), 6.90-7.08 (m, 2H), 7.27-7.56 (m, 12H) ), 7.70 (ddd, J = 12.5, 8.0, 2.0 Hz, 4H), 7.94 (dd, J = 12.5 and 8.0 Hz); ³¹ P { ¹ H] -NMR (145.79 MHz, CDCl ₃ ): δ 26.72 (br d, ⁴ J _{P, F} = 6.0 Hz); ¹⁹ F NMR (188.14 MHz, CDCl ₃ ): δ -108.5 (m); MS (+ FAB, MeOH / NBA): m / e (rel. Int.) [705 (14), 704 (20), 703 (53), 702 (37), 701 (93), 700 (49), 699 (100), 698 (60), 697 (30) M-Cl for different isotopes of Pd and Cl], [668 (7), 667 (11), 666 (14), 665 (10), 664 (23 ), 663 (16), 662 (10) M-2Cl for different isotopes of Pd]; IR (KBr): 3060 (w), 1450, 1437, 1420, 747, 696, 507, 499, 487 cm ^-1 , element analysis (found / calculated for C ₃₆ H ₂₆ Cl ₂ F ₂ P ₂ Pd ): C 58.9 / 58.76, H 3.8 / 3.56, Cl 9.6 / 9.64, F 4.7 / 5.16.

[(R) - (6,6'-difluoro-biphenyl-2,2'-diyl) bis (diphenylphosphine)] - dichloride palladium (II) (R) - (+) - 11

Deoxygenated 10 N hydrochloric acid (22 ml) was added to the refluxing solution of (S, R) - (+) - 10 (408 mg, 0.48 mmol) in deoxygenated acetone (20 ml). A yellow precipitate formed after a few minutes. The mixture was refluxed for 2 hours. Treatment as described for (S) -11 gave bright yellow crystals (346 mg, 0.47 mmol, 98% yield), mp. 310-311 ° C (dec.), [Α] _D 25 + 311.5 ( c 0.495, dichloromethane); the spectra were congruent with those of (S) -11 .

(S) - (6,6'-difluoro-biphenyl-2,2'-diyl) bis (diphenylphosphine) (S) - (+) - 5

1,2-bis (diphenylphosphine) ethane (dppe) (508 mg, 1.27 mmol, 0.8 equiv) was added to a solution of (S, S) -10 (1.53 g, 1.59 mmol) in deoxygenated dichloromethane (20 ml) added. The clear solution obtained was stirred at 20-25 ° C for 16 h. The course of the reaction could be monitored by TLC [100% toluene, R _f : (S, S) -10 (0.00), dppe (0.61), 5 (0.80)], which was a quantitative reaction of dppe, indicated the presence of 5 and a baseline spot (palladium complexes). Deoxygenated cyclohexane (20 ml) was added and the mixture was filtered through a frit containing a bed of silica gel (35-70 µm, 13.5 g). The silica bed was washed with deoxygenated dichloromethane / cyclohexane (1: 1, 4 x 20 ml). The filtrates were combined and evaporated in vacuo. Methanol (3 ml) was added to the residue and the solvent was evaporated in vacuo; there was a colorless solid (657 mg, 1.18 mmol, yield 93%), mp. 161-163 ° C. An analysis sample was prepared by recrystallization (0 ° C, 12 h) from boiling toluene / ethanol (4: 5), mp. 164-165 ° C, [α] _D 25 + 114.9 (c 0.99, toluene) , see. Table 1. The NMR spectra were congruent with those of (R / S) -5. The DC and the HPLC [cf. (R / S) -5] gave 100% chemical purity. The oxidation to bis (phosphine oxide) (S) -4 followed by HPLC analysis of the chiral phase gave 100% ee (see below). When one (S, S) -10 under the same conditions with 1.0 equiv. dppe reacted, considerable amounts of dppe were not reacted (DC) and it was difficult to remove them from the reaction product.

Configuration stability of (S) -5 when heated in solution

A solution of optically pure (S) -5 (44.2 mg) in tetralin (10 ml, boiling point 207 ° C) was refluxed in an argon atmosphere for 2.5 hours. The specific rotation of the solution remained constant and a sample taken after the oxidation to bis (phosphine oxide) (S) -4 gave 100% ee after HPLC analysis of the chiral phase.

The configuration stability was also observed after a solution of (S) -5 in toluene was left under argon for 12 days and this solution was then heated at 100 ° C for 8 h, and as a solution of (S) -5 in Mesitylene (boiling point 164 ° C) was refluxed for 3 hours.

Attempt to prepare (S) -5 by reacting Palladium dichloride complex (S) -11 with potassium cyanide

To a solution of (S) -11 (87 mg, 0.12 mmol) in dichloromethane (10 ml) was added potassium cyanide (30 mg, 0.46 mmol), water (5 ml) and methanol (10 ml) (all solvents deoxygenated). The clear solution was stirred for 2 hours. The TLC showed no formation of 5 . Potassium cyanide (250 mg) was added and the solution was stirred for 16 h: no reaction.

(R) - (6,6'-difluoro-biphenyl-2,2'-diyl) bis (diphenylphosphine) (R) - (-) - 5

In an analogous procedure to that described for (S) - (+) - 5, the reaction of the chloride (S, R) -10 (748 mg, 0.88 mmol) with dppe (282 mg, 0.71 mmol, 0) , 8 equiv.) In dichloromethane (20 ml) the title compound (390 mg, 0.70 mmol, yield 99%), mp. 164-165 ° C, [α] _D 25 -114.8 (c 1.03, toluene), NMR spectra congruent with those of (R / S) -5 and (S) -5 . TLC and HPLC showed 100% chemical purity. The oxidation to the bis (phosphine oxide) (R) -4 followed by HPLC analysis of the chiral phase gave 100% ee (see below).

(S) -6,6'-difluoro-biphenyl-2,2'-diyl) bis (diphenylphosphine) (S) - (-) - 4

Methanol (5 ml) and then 35% aqueous hydrogen peroxide solution (1 ml, 11.6 mmol) were added to the solution of (S) -5 (101 mg, 0.18 mmol) in toluene (2 ml). The mixture was stirred for 4 hours. The DC [cf. (R / S) -5] gave the compound the title and trace residues of 5 and monooxide. Hydrogen peroxide (1 ml) was added and stirring continued for 1 h. The DC now showed a quantitative oxidation. The solution was washed with saturated aqueous sodium sulfite solution (3 × 3 ml) and 1N hydrochloric acid (2 × 2 ml). The solvent was evaporated in vacuo. The residue was extracted with chloroform (3 x 15 ml). The extracts were combined and washed with saturated aqueous sodium bicarbonate solution (2 × 10 ml) and with water (2 × 10 ml) and dried over magnesium sulfate. The solvent was evaporated in vacuo to give a colorless solid (100 mg, 0.17 mmol, yield 94%), mp. 275-277 ° C, [α] _D 20 -11.8 (c 0.92, chloroform ).
¹ H NMR (Table 2); ¹³ C NMR (Table 3); ¹⁹ F { ¹ H} -NMR (470.59 MHz, CDCl ₃ ): δ-110.21 (J _{F, P} = 6.6 Hz); ³¹ P { ¹ H} NMR (202.46 MHz, CDCl ₃ ): δ 28.89 (J _{F, P} = 6.6 Hz).

The HPLC of the chiral phase (250 × 4.6 mm DNBPG Bakerbond, 1.0 ml / min n-hexane + ethanol (20 + 1), det. 254 nm) in comparison with the racemic reference sample (R / S) - 4 gave 100% (S) -4 (t _ret 25.50 min) and 0% (R) -4 (t _ret 23.63 min). An analytical sample was obtained by recrystallization (0 ° C, 12h) from boiling dichloromethane / ethyl acetate (3: 1), mp 282-283 ° C, [α] _D 20 -11.3 (c 0.96, chloroform); [α] ₃₆₅ 20 +57.0 (c 0.59, methanol).

(R) - (6,6'-difluoro-biphenyl-2,2'-diyl) bis (diphenylphosphine) (R) - (+) - 4

Analogously, the oxidation of (R) -5 gave a colorless solid, mp. 282-283 ° C, [α] _D 20 +11.3 (c 0.83, chloroform); [α] ₃₆₅ 20 -56.5 (c 0.57, methanol). The ¹ H, ¹³ C { ¹ H}, ¹⁹ F { ¹ H}, and ³¹ P { ¹ H} NMR spectra in CDCl ₃ were congruent with those of (S) -4 and (R / S) - 4th HPLC of the chiral phase gave 100% (R) -4.

Rhodium (I) - (R) - (-) - 5 catalyzed asymmetric Hydroboration / oxidation of p-methoxystyrene

The solution of p-methoxystyrene (12) (671 mg, 5.0 mmol), (1,5-cyclooctadiene) (2,4-pentanedionate) rhodium (I) (31.0 mg, 0.10 mmol) and (R) - (-) -5 (61.4 mg, 0.11 mmol) in deoxygenated, dry THF (6 ml) is refluxed under argon for 90 min. The solution is then cooled and an IN solution of catecholborane in THF (10.0 ml, 10.0 mmol), which has previously been purged with argon (10 min), is added dropwise over 5 min at 0 ° C. The mixture is stirred for 90 min at 0 ° C under argon. TLC (cyclohexane / ethyl acetate 1: 1; R _f 12: 0.66, 13: 0.41, 14: 0.30) shows the quantitative reaction of 12 . The solution is cooled to -20 ° C and ethanol (10 ml), 4N aqueous sodium hydroxide solution (5 ml) and 36% aqueous hydrogen peroxide solution (10 ml) are added in succession at ≤ 5 ° C. The mixture is stirred at ambient temperature overnight and then extracted with diethyl ether (3 × 50 ml). The extracts are pooled and washed with IN sodium hydroxide (4 x 25 ml), water (20 ml) and brine (20 ml), dried over sodium sulfate and the solvent is evaporated. The residue (780 mg of pale brown oil) is subjected to molecular distillation (bath 60-80 ° C./≈10 ^-3 torr) and gives a colorless oil (682 mg, 4.48 mmol, yield 90%) and a brown residue, which crystallizes (98 mg). TLC and ¹ H-NMR show that the distillate consists of 13 and 14 (ratio 78:22), [α] _D 20 +27.7 (c 1.17, chloroform). Correction for 22% achiral 14 gives [α] _D 20 _corr +35.5 (c 0.91, chloroform). A comparison with the literature shows that 13 ≈67% ee has the (R) configuration. The HPLC analysis of the chiral phase [250 mm length, 4.6 mm inner diameter, column Chiralcel OD 10 µm (Daicel); 0.5 ml / min n-hexane / ethanol (100 + 0.8), 40 ° C, det. 254 nm] gives 68.3% (R) - (+) - 13 (t _ret 62.80 min), 8.5% (S) - (-) -13 (79.40 min) and 23.2% 14 (66.14 min). This corresponds to 77.8% ee of the (R) - (+) - isomer of 13.

Hydrogenation of 2-benzylidenesuccinic acid 4 - [(4-BOC-amino] -1-piperidide, catalyzed by the neutral rhodium (I) - (R) - (-) - 5 complex

(R) - (-) -5 (30.1 mg, 0.054 mmol) is added to the suspension of di-µ-chloro-bis [(cycloocta-1c, 5c-diene) rhodium (I)] (12.3 mg , 0.025 mmol) in deoxygenated methanol / benzene (3: 1) (20 ml) and stirred under argon, so that a clear solution is formed within 15 min. In a hydrogenation flask, 2-benzylidenesuccinic acid 4 - [(4-BOC-amino) -1-piperidide (1.94 g, 5.0 mmol) is dissolved in deoxygenated methanol / benzene (3: 1) (20 ml). The clear catalyst solution is added under argon and the reaction mixture is shaken from a hydrostatic hydrogenation device ⁵³ under 1 bar of hydrogen: no hydrogen is taken up within 6 hours. The hydrogenation flask is placed in a shake autoclave under argon; 150 bar of hydrogen is allowed to act for 2 days. The solvent is evaporated in vacuo and the solid residue is dissolved in tert-butyl methyl ether (40 ml). The cold (0 ° C) solution is washed with 0.5N hydrochloric acid (10 ml) and with water (10 ml) and dried (MgSO ₄ ). The solvent is evaporated to give a solid (1.80 g, 4.16 mmol, 92% crude yield). HPLC ⁵³ shows quantitative hydrogenation. HPLC of chiral phase ⁵³ gives 22% ee of the (R) - (+) configuration.

Claims (9)

1. A compound of the formula II

   

   in which the phenyl rings of the biphenyl molecule can be substituted with up to 6 additional fluorine and/or chlorine atoms.
2. A process for the preparation of a compound of the formula II as claimed in claim 1, which comprises reacting a compound of the formula 4

   

   in which X is F, with Cl₂Si(CH₃)H, NBu₃, in an organic solvent under an inert gas or alternatively boiling the compound of the formula 4 under reflux with HSiCl₃ and NBu₃ in an organic solvent to give the compound of the formula II, where the phenyl rings of the biphenyl molecule may be substituted with up to 6 additional fluorine and/or chlorine atoms.
3. A process for the preparation of a compound of the formula 4 as in claim 2, which comprises heating a compound of the formula 3

   

   in an inert solvent with the addition of a transition metal, preferably Cu, where the compound of the formula 3 can be substituted in position 4, 5 and/or 6 with up to 3 fluorine and/or chlorine atoms.
4. A process for the preparation of a compound of the formula 3 as in claim 3, which comprises reacting a compound of the formula 2

   

   with lithium diisopropylamide in an inert solvent, preferably in THF, and then with iodine, where the compounds of the formulae 2 and 3 can be substituted in postiion 4, 5 and/or 6 with up to 3 fluorine and/or chlorine atoms.
5. A compound of the formula 4

   

   in which X is F and in which the phenyl rings of the biphenyl molecule can be substituted with up to 6 additional fluorine and/or chlorine atoms.
6. A complex of rhodium(I), ruthenium(II), palladium(II) or palladium(0) with a compound of the formula II.
7. A process for the preparation of a complex as claimed in claim 6, which comprises reacting a compound of the formula II as claimed in claim 1 with suitable complexes having readily displaceable ligands, or comprises obtaining the complexes from the corresponding palladium complex by HCl-induced elimination of the N,N-dimethyl-·-phenylethylamine ligand.
8. The use of a complex as claimed in claim 6 as a catalyst.
9. The use of a complex as claimed in claim 6 as a catalyst for symmetrical or asymmetrical addition, substitution, rearrangement or coupling reactions.